1. Field of the Invention.
This invention relates to devices for measuring the concentration of certain biochemical constituents in samples. More particularly, the invention relates to a fiber optic device and related method which utilizes a reflective surface to enhance the emitted signal and to reduce the effects of excitation light when the sensor is operating.
2. Description of the Prior Art.
It has become increasingly important in analytical and clinical chemistry to have the capability of remote sensing of chemical and physical parameters. Some methods of performing this type of sensing have been known, such as potentiometry, amperometry, piezo-electric mass determination, conductivity and measurement of reaction enthalpy.
In addition to these methods, optical fibers can be used for remote sensing of analytes and other substances. Optical sensors have certain advantages over electrochemical sensors. For example, optical sensors do not require reference cells and optical sensors are immune to electromagnetic interferences. Further, the use of optical fibers can be advantageous when the samples are relatively inaccessible, for instance, in case of in vivo tests. Optical fiber waveguides allow the transportation of an optical signal over large distances from the sample to an associated meter, for example. Optical fibers can be exposed to varying environments without suffering substantial destruction or deterioration as a result. Optical fibers are also biocompatible which makes them desirable for use in invasive medical procedures. For a general discussion of sensors and of optical fiber sensors in particular see Wolfbeis, Fibre-optic Sensors in Biomedical Sciences, Pure and Appl. Chemistry, Vol. 59, No. 5 pp. 663-672 (1987).
It has been known to provide optical fiber sensors of various types. U.S. Pat. No. 4,334,438, the inventor of which is one of the co-inventors hereof, is hereby incorporated herein by reference. This patent U.S. Pat. No. 4,334,438 relates to a fiber optic sensor having a chamber containing a dialysis membrane which allows selected plasma constituents to pass therethrough and enter the chamber. The chamber contains specific receptor sites in the form of binding agents each of which reversibly binds with one of the plasma constituents. The chamber also contains competing ligands which are dye-labeled. They compete with the plasma constituents for the specific receptor sites on the binding agents. The competing ligands are chosen for their particular optical properties and molecular size so that they do not escape back out of the sensor into the bloodstream. The intensity of light emitted from or absorbed by the receptor-site/competing ligand complexes or the free competing ligand alone can be measured by a fluorimeter. This measurement gives a quantitative indication of the concentration of plasma constituents in the blood.
One limitation of this system is that the response time is on the order of minutes due to the time it takes for diffusion of the molecules being studied across the membrane and along the chamber. Further, as the fluorescently labeled compound is bound to the wall, the optical fiber must be inserted exactly straight inside the hollow fiber so that the amount of baseline fluorescence due to the dye-labeled competing ligand bound to the wall is minimized. Further, the skin of the membrane must remain immersed in a buffer solution. Otherwise, if it is exposed to air, the membrane begins to dry and diffusion of the analyte into the sensor is dramatically affected. Because of this, the assembly must be glued together while it is submerged in the buffer. The glue seams must form a tight seal because with any leak, the chemical constituents of the sensor can escape. The hollow fiber configuration can also exhibit lack of stability such that any movement of the sensor while in use affects the signal response. In addition, during assembly the proteins which are immobilized are pumped through the fiber with pressure. This flow method results in variations in the amount of immobilized material along the inside wall, due to variations in the spongy surface. There remains a need, therefore, for a sensor which overcomes those disadvantages.
It has also been known to provide other types of fiber optic sensors. For example, U.S. Pat. No. 4,892,383 discloses a fiber optic sensor which includes a modular reservoir cell body and a semi-permeable membrane, however, the sensor requires use of a reagent which precludes reversibility. See also U.S. Pat. No. 4,892,640 which discloses a sensor for determining electrolytic concentrations using an ion selective membrane.
U.S. Pat. No. 4,849,172 discloses an optical sensor having a gas permeable silicone matrix that contains a high concentration of an optical indicator consisting essentially of a mixture of derivatives of a polynuclear aromatic compound U.S. Pat. No. 4,853,273 discloses another type of sensor involving enhancement of a light signal response by incorporating a partially reflecting, partially transmitting medium between a coupling structure and an optically dense body.
Optical sensors based on generating a resonance signal in a metallic medium have also been known. See U.S. Pat. No. 4,877,747. Other sensors based on detection of refractive index charges in gaseous liquids, solids or porous samples have been known. See U.S. Pat. No. 4,815,843 and U.S. Pat. No. 4,755,667. Sensors for measuring salt concentrations have also been known. U.S. Pat. No. 4,572,106.
U.S. Pat. No. 4,577,106 discloses a remote multiposition information gathering system for obtaining thermometric information from remote locations using fiber optics.
U.S. Pat. No. 4,861,727 discloses a luminescent oxygen sensor using a lanthanide complex.
Other methods of measuring concentrations of biochemicals in blood include withdrawing blood from the patient and then analyzing it. For example, U.S. Pat. No. 3,785,772 discloses a device having a pair of syringes to withdraw blood from a patient, and a dialysis membrane to separate a particular blood constituent from the blood, a reactant which reacts with the chosen blood constituent to form a reactant--blood constituent complex the concentration of which is proportional to the concentration of the blood constituent. This system requires replacement of the reactant after each measurement because the reactant and the blood constituent form an irreversible complex. In addition, the system cannot give measurement of an instantaneous change in the concentration of the blood constituent because of the time taken to remove the blood from the body and obtain a reaction with the reactant.
U.S. Pat. No. 3,638,639 also shows measurement of blood constituents outside the body. In this system, a catheter is inserted into the blood and lipids are passed through a membrane in the catheter and are dissolved in a solvent which is sent out of the body to be analyzed.
U.S. Pat. No. 3,939,350 shows a system for carrying out immunoassays using fluorescense to indicate the presence of a ligand to be detected. An analog liquid is bound to a transparent sheet and contacted with an aqueous assay solution containing the ligand to be detected associated with fluorescent molecules. The ligands become bonded to the sheet and light is passed there through to cause fluorescence.
U.S. Pat. Nos. 3,123,866, 3,461,856 and 3,787,119, all disclose means to measure properties of the blood in vivo. These comprise optical catheters inserted into the blood for measuring the intensity of light reflected from the blood thereby indicating the blood's oxygen content. None of the aforementioned patents, however, are specifically designed for measuring the concentration of plasma constituents, such as glucose, in a continuous, reversible manner.
Despite these prior art methods and devices, there remains a need for an optical fiber sensor which has increased sensitivity and a shorter response time. Further there remains a need for a device where the active element is of shorter length and a sensor which is easier to assemble than conventional designs. There also remains a need for a sensor which provides greater excitation signals and simultaneously captures a greater percentage of the emitted light from a molecule to be analyzed by reflecting back into the fiber light which is emitted in directions opposite to the fiber location. There remains a further need for a device and method which may be used to measure either free dye-containing molecules or bound dye-containing molecules and which has the capability of providing continuous monitoring of the concentration of an analyte.